US3158605A - 2, 19-cyclo-derivatives of cortical hormones - Google Patents

2, 19-cyclo-derivatives of cortical hormones Download PDF

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US3158605A
US3158605A US231829A US23182962A US3158605A US 3158605 A US3158605 A US 3158605A US 231829 A US231829 A US 231829A US 23182962 A US23182962 A US 23182962A US 3158605 A US3158605 A US 3158605A
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cyclo
dione
acetoxy
isopropylidenedioxy
chloro
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Alexander D Cross
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Roche Palo Alto LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

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  • the present invention relates to novel cyclopentanophenanthrene derivatives and to a process for the production thereof.
  • the present invention relates to novel 2,19-cyclo-derivatives of cortical hormones.
  • novel compounds of the present invention are represented by the following formula:
  • Y represents hydrogen, fluorine or chlorine
  • W represents a B-hydroxyl group or a keto group
  • X represents hydrogen, fluorine or chlorine all having a or fi-configurations
  • Z represents a double bond or a saturated linkage between C-4 and C-5
  • Z represents a double bond or a saturated linkage between 0-6 and C-7
  • R represents a hydroxyl group
  • T represents hydrogen, a-hydroxyl, Ot-QCYlOXY, a-methyl or ,8- methyl
  • T and R together represent the group in the 16a,l7apositions wherein R and R each represents hydrogen or a'hydrocarbon residue of up to 8 carbon atoms of straight, branched, cyclic or mixed cyclic aliphatic chain, or aromatic, such as methyl, ethyl, isopropyl, phenyl, methyl-cyclohexyl and the like; and R represents
  • the acyl and acyloxy groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclicaliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen.
  • Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclophentylpropionate, aminoacetate, and fi-chloropropionate.
  • the compounds represented by the above formula are valuable cortical hormones with high anti-inflammatory,
  • novel compounds of the present invention are pre- 3,158,665 Patented Nov. 24, 1964 pared by the process illustrated by the following formula scheme:
  • the starting compound (I) which is a 2,19-cyclo-allopregnam-l7u-ol- 3,20-dione, a 2,19-cyclo-A -pregnen-17m-ol-3,20-dione or a 2,19-cyclo-A -pregnadien-17a-ol-3,20-dione derivative, is treated with iodine in the presence of calcium oxide to give the corresponding 21-iodo derivative which upon treatment with potassium acetate, in a suitable solvent, such as acetone, preferably at reflux temperature, affords the corresponding 2l-acetoxy-Z,l9-cyclo-pregnan-l7a-oL 3,20-dione deriavtive (II).
  • a suitable solvent such as acetone
  • M -derivative is treated With N-bromoamide or imide, such as N-bromoacetamide, in the presence of perchloric acid, in an inert solvent, such as for example dioxane, to give the corresponding 9ob1'0mO-l1fi-Ol which upon treatment with the mild base, such as potassium acetate in acetone, preferably at reflux temperature, affords the corresponding 2,l9-cyclo-9/3,1lfl-oxido pregnen derivative.
  • N-bromoamide or imide such as N-bromoacetamide
  • a hydrogen halide such as hydrogen fluoride or hydrogen chloride
  • a suitable inert organic solvent e.g. methylene chloride or chloroform
  • the compounds of the present invention having a 21- acyloxy group may be saponified by conventional treatment with a base to produce the corresponding 21-free alcohols which, in turn, may be acyl-ated conventionally in pyridine with an acylat-ing agent to give the corresponding 21-acylates, wherein the acyl group may be different from the previously saponified one.
  • Example I A cooled solution of 4 g. of l6a,17a-isopropylidenedioxy-2,l9-cyclo-allopregnane-3,ZO-dione (obtained according to my copending US. pat. appl. Ser. No, 231,828 filed of even date) in 30 cc. of tetrahydrofuran and 18 cc. of methanol was treated under continuous stirring with 6 g. of pure calcium oxide, in small portions, and then with 6 g. of iodine. The stirring was continued at room temperature until the solution turned pale yellow. The mixture was poured into ice water containing 18 cc. of acetic acid and 2 g. of sodium thiosulfate.
  • pregnadien-H a ol-3,2G- cyclo A -pregnadien-17 adione. ol-3,20-dione.
  • Example 11 The following solutions A, B and C were prepared using distilled water as solvent: solution A was prepared by mixing 425 cc. of a 1.742% dipotassic phosphate solution (K HPO with 75 cc. of 1.3 8% monosodic phosphate; solution B was prepared by diluting a mix-- ture of 1 1t. of 4.5% sodium chloride solution, 40 cc. of a 5.75% potassium chloride solution and 10 cc. of a 19.1% magnesium sulfate, to a volume of 5 1t; solution C was prepared by dissolving 20.9 g. of fumaric acid and 14.4 g. of sodium hydoxide in 1 it. of water and diluting the solution to 1.2 lt. Then 475 cc. of solution A, 4.32 It, of solution B and 1.2 lt. of solution C were mixed.
  • K HPO dipotassic phosphate solution
  • solution B was prepared by diluting a mix-- ture of 1 1
  • pound No. 1 dissolved in 5.35 parts of propylenglycol;
  • Example III g. of 21-acetoxy-16a,17a-isopropylidenedioxy-2,19- cyclo-allopregnan-11,B-0l-3,20-dioue (Cpd. No. 28) was dissolved with slow heating in 125 cc. of dimethyl-formamide, the mixture was cooled, 4.2 g. of mesyl chloride and 5 cc. of pyridine were added and the solution was kept at 80 C. for half an hour. The reaction mixture was cooled, water was added and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated.
  • Example IV In a polyethylene flask, adapted with magnetic stirrer, there was dissolved 1.8 g. of 21-acetoxy-913,1113-oxido- 1601,1701 isopropylidenedioxy 2,19 cyclo allopregnane-3,20-di0ne (Cpd. No. 56), in 30 cc. of methylene chloride, the solution was cooled to 0 C. and a solution of 2.11 g. of anhydrous hydrogen fluoride in 3.7 cc. of tetrahydrofurane cooled in a Dry-Ice acetone bath (70 C.) was added over a period of 20 minutes with constant stirring. The mixture was stirred at a temperature lower than C.
  • Example V A solution of 1 g. of 21-acetoxy-16a,-1701-isopropylidenedioxy-Z,19-cyclo-allopregnan-1113-ol-3,20-di0ne (Cpd. No. 28) in 10 cc. of acetone was cooledto 0 C. and treated under an atmosphere of nitrogen and with stirring, with a solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture. It was stirred for 5 minutes further at 0-5" C. and diluted with water.
  • Example XIII The Compounds Nos. 247, 248 and 249 were treated in accordance with Example X, thus giving respectively:
  • Example XIV A mixture of 1 g. of Compound No. 247, 50 cc. of freshly distilled acetophenone and 0.5 cc. of 72% perchloric acid was stirred at room temperature for 1 hour. The resulting mixture was washed with sodium bicarbonate solution and with water to neutrality, then it wassteam distilled and the product extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane yielded the 16,17-acetophenonide of 2,19- cyclo allopregnane 11,8,16oc,l7oc,21 tetrol 3,20 dione (Cpd. No. 262).
  • Y is selected from the group consisting of hydrogen, fiuorine and chlorine; W is selected from the group consisting of a B-hydroxyl group and a keto group;
  • X is a member of the group consisting of hydrogen, (X-fluO- rine, fl-fluorine, a-chlorine and fl-chlorine;
  • Z is selected from the group consisting of a double bond and a saturated linkage between C-4 and C-5;
  • Z is selected from the group consisting of a double bond and a saturated linkage between C-6 and C-7, and when Z is a saturated linkage, Z is a saturated linkage;
  • R is a hydroxyl group;
  • T is selected from the group consisting of hydrogen, t-hydroxyl, tat-hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms, u-methyl and B-methyl;
  • T and R together form the group in the 16a,17a-positions wherein R and R are selected from the

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description

United States Patent 3,158,605 2,19-CYCLO-DERIVA'I'IVES QF CORTICAL HGRMQNES Alexander D. Cross, Mexico (Iity, Mexico, assignor to Syntex Corporation, Panama, ?anama, a corporation of Panama No Drawing. Filed Get. 19, 1962, Ser. No. 231,829 20 (Ilaims. (Cl. Brill-239.55)
The present invention relates to novel cyclopentanophenanthrene derivatives and to a process for the production thereof.
More particularly the present invention relates to novel 2,19-cyclo-derivatives of cortical hormones.
The novel compounds of the present invention are represented by the following formula:
CHQOR In the above formula Y represents hydrogen, fluorine or chlorine; W represents a B-hydroxyl group or a keto group; X represents hydrogen, fluorine or chlorine all having a or fi-configurations; Z represents a double bond or a saturated linkage between C-4 and C-5; Z represents a double bond or a saturated linkage between 0-6 and C-7; when Z is a saturated linkage Z is also a saturated linkage; R represents a hydroxyl group; T represents hydrogen, a-hydroxyl, Ot-QCYlOXY, a-methyl or ,8- methyl; T and R together represent the group in the 16a,l7apositions wherein R and R each represents hydrogen or a'hydrocarbon residue of up to 8 carbon atoms of straight, branched, cyclic or mixed cyclic aliphatic chain, or aromatic, such as methyl, ethyl, isopropyl, phenyl, methyl-cyclohexyl and the like; and R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.
The acyl and acyloxy groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclicaliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclophentylpropionate, aminoacetate, and fi-chloropropionate.
The compounds represented by the above formula are valuable cortical hormones with high anti-inflammatory,
' low catabolic, glycogern'c and thymolytic activitites. In
addition, they are anti-androgenic, anti-gonadotropic and anti-estrogenic hormones. Furthermore, they have high topical activity in skin disorders such as psoriasis, allergic dermatitis and the like.
The novel compounds of the present invention are pre- 3,158,665 Patented Nov. 24, 1964 pared by the process illustrated by the following formula scheme:
CH (FHZORI (5:0 0:0 Inn-R I-v-R 3 T T (llHgOR CH OR C=O =0 .IIR 0R T 1 10f MN '1 IV III In the above formulae R, R T, Y, Z, Z and X have the same meaning as previously defined.
In practicing the process outlined above, the starting compound (I) which is a 2,19-cyclo-allopregnam-l7u-ol- 3,20-dione, a 2,19-cyclo-A -pregnen-17m-ol-3,20-dione or a 2,19-cyclo-A -pregnadien-17a-ol-3,20-dione derivative, is treated with iodine in the presence of calcium oxide to give the corresponding 21-iodo derivative which upon treatment with potassium acetate, in a suitable solvent, such as acetone, preferably at reflux temperature, affords the corresponding 2l-acetoxy-Z,l9-cyclo-pregnan-l7a-oL 3,20-dione deriavtive (II). p
The latter derivative upon incubation with adrenal glands in a suitable medium, e.g. an aqueous solution of alkali metal phosphates and chlorides and magnesium sulfate, mixed with an aqueous solution of fumaric acid and sodium hydroxide, for a period of time of the order of 3 hours at approximately 28-37 C., yields the correspondin g Qlacetoxy-2,19-cyclopregnane-1lfl,l7a-diol-3,20-dione (III: Y-=H). The latter 115-01 (III: Y=H) is treated with mesyl chloride in dimethyl formamide and pyridine at approximately C. for about half an hour to produce the corresponding 21-acetoxy-2,19-cyclo-A pregnen-l7a-ol-3,20-dione derivative. The last named M -derivative is treated With N-bromoamide or imide, such as N-bromoacetamide, in the presence of perchloric acid, in an inert solvent, such as for example dioxane, to give the corresponding 9ob1'0mO-l1fi-Ol which upon treatment with the mild base, such as potassium acetate in acetone, preferably at reflux temperature, affords the corresponding 2,l9-cyclo-9/3,1lfl-oxido pregnen derivative.
The latter 95,11,8-oxido compound, upon treatment with a hydrogen halide, such as hydrogen fluoride or hydrogen chloride, in a suitable inert organic solvent, e.g. methylene chloride or chloroform, yields the corresponding 21-acetoxy-9a-ha'lo-2,19-cyolo-pregnane-l 1/3, 1 7oc-di0l- 3,20-dione derivative (III: Y=halogen). The llfi-hydroxyl group of the latter compounds as Well as of the- 9a-unsu-bstituted 11,Bols (III: Y=H) is oxidized pref-.
l7 x-ketonide grouping, yield the corresponding 16,17udiols by conventional treatment with an acid, such as acetic acid. The obtained diolsfupon conventional esterification in pyridine with an acylating agent, as for example acetic anhydride or caproic anhydride, afiord the corresponding l6-acylates.
The latter l6a,l7a-diols upon conventional condensation with a ketone or aldehyde, such as benzaldehyde, acetophenone, methyl-ethyl ketone, acetone, and the like, in the presence of an acid, yield the corresponding 16u,l7otmethylenedioxy derivatives, wherein the substituents in the methylenedioxy group may be d-iiterent from those of the previously hydrolyzed ketonide grouping.
The compounds of the present invention having a 21- acyloxy group, may be saponified by conventional treatment with a base to produce the corresponding 21-free alcohols which, in turn, may be acyl-ated conventionally in pyridine with an acylat-ing agent to give the corresponding 21-acylates, wherein the acyl group may be different from the previously saponified one.
The following specific examples serve to illustrate the present invention, but are not intended to limit the scope thereof:
Example I A cooled solution of 4 g. of l6a,17a-isopropylidenedioxy-2,l9-cyclo-allopregnane-3,ZO-dione (obtained according to my copending US. pat. appl. Ser. No, 231,828 filed of even date) in 30 cc. of tetrahydrofuran and 18 cc. of methanol was treated under continuous stirring with 6 g. of pure calcium oxide, in small portions, and then with 6 g. of iodine. The stirring was continued at room temperature until the solution turned pale yellow. The mixture was poured into ice water containing 18 cc. of acetic acid and 2 g. of sodium thiosulfate. After stirring for 15 minutes the solution was decanted and the precipitate was collected by filtration, thus giving the 2l-iodo derivative of the starting compound. This compound was mixed with 80 cc. of acetone and 12 g. or" recently fused potassium acetate and the mixture was refluxed for 8 hours, concentrated to a small volume, diluted with Water and extracted with ethyl acetate; the extract was washed with water, dried over anhydrous sodium sulfate and concentrated until crystallization started. The precipitate was collected and crystallized from methanol water, thus yielding 2l-acetoxy-16a,l7a-isopropylidenedioxy-2,19-cyclo-allopregnane 3,20 dione (Compound No. 1).
The starting compounds listed under I (obtained in accordance with the aforesaid patent application) were treated by the above procedure, furnishing firstly the corresponding 21-iodo derivatives and thereafter, respectively, the products set forth under II.
(SB-chloro-IG a-mcthyl-ZJQ- 9 cyclo-A -pregncn-17 o:-ol- 3,20-dione.
fifldluoro-IG 11,17 a-isopropylidenedioxy-2,19-cyc1o-A preguenc-3,20-dione.
I Cpd. II
3,20-dione.
6 a-chloro16 d-l? a-isopropyli- 13 21-acet0xy-6 a-chlorodfi a,17 adcnedioxyQJS-cyclo- A' isopropylidenedioxy-2, 19- pregnene-3,20-dionc. gsl elo- N-pregnenc-Sflflone.
6 a-chloro-2,19-cyclo- A 14 21-acetoxy-6 oz-chlOIO-Z, 19-
prcwon-U 0c0l3,20-dl0110. cyolo- A -pregnen-l7 a-ol- 3,20-dione.
6 uc-Cl1l0t -16 a-methyl2,19- 15 21-acetoxy-6 a-chloro-IG acyclo- A -pregncn-17 a-Olmethyl-2,19-cyclo- N-preg- 3,20-dione. non-17 a-0l-3,20-dionc.
3,20-dione.
6 a-fiuoro-lfi a-methyl-2, 19- 18 2l-acetoxy-6 a-fluoro-lfi :xcyclo- A -pregnen-17 a-Olmethyl-2,19-cyclo- A 3,20-dione. pregnend? a-ol-3,2D-dione.
6-chl0ro-16 a,17 a-isoprop yli- 19 2l-acetoxy-6-ch1oro-16 (1,17 0:-
denedioxy-ll eyclo- A isopropylidcnedioxy-2,l9- pregnadiene-3,20-diona cyclo- A -pregnadienc- 3,20-di0ne. 6-chloro-2,19-eyclo- A 20 21-acetoxy-6-uhloro-2,l9-
pregnadien-H a ol-3,2G- cyclo A -pregnadien-17 adione. ol-3,20-dione.
fi-chloro-lo a-methyl-2, 19- 21 2l-acetoxy-6-chloro-l6 aeyclo- 13 "-p rcgnadicn-IT amethyl-2,l9-cyclo- A 01-3, 20 dioue. pregnadien-l? owl-3,20-
dione.
G-fluoro-lfi 04,17 a-isopropyli- 22 2l-acetoxy-6-iluoro-l6 11,17 ordenedioxy-2,19-eyclo- A isopropylideuedioxy-2,19- pregnadieue-3,20-dione. eyclo- A -pregnadiene- 3,20-dione.
ol-3,20-di0nc.
6-iluoro-16 a-rnethy1-2,19- 24 2l-acetoxy-G-fluoro-16 o:-
eyclo- A -pregnadien-H amethyl-2,l9-cyclo- A ol-3,2O-dione. pregnadien-17 owl-3,20-
dione.
1G a, 17 a-isopropylidenedioxy- 25 21-acetoxy-16 a,17 a-isopropyli- 2,19-eyelo- A -pregnadienedenedioxy-2,19-cyclo- A 3,20-dione. pregnadiene-3,20-dione.
2, 9-cyclo- A -preguadien- 26 21-aeetoxy-2,19-cyclo- A I 17 a-0l-3,20-dione. gregnadien-l? moi-3,20-
lone.
16 wmethyl-ZJQ-cyclo- A 27 2l-acetoxy-1fi a-methy1-2,1 9-
prcgnadien-l7 a-ol-3,20- cyclo- N' -pmgnadien-U adione. ol-3,20-dione.
Example 11 The following solutions A, B and C were prepared using distilled water as solvent: solution A was prepared by mixing 425 cc. of a 1.742% dipotassic phosphate solution (K HPO with 75 cc. of 1.3 8% monosodic phosphate; solution B was prepared by diluting a mix-- ture of 1 1t. of 4.5% sodium chloride solution, 40 cc. of a 5.75% potassium chloride solution and 10 cc. of a 19.1% magnesium sulfate, to a volume of 5 1t; solution C was prepared by dissolving 20.9 g. of fumaric acid and 14.4 g. of sodium hydoxide in 1 it. of water and diluting the solution to 1.2 lt. Then 475 cc. of solution A, 4.32 It, of solution B and 1.2 lt. of solution C were mixed.
Adrenal glands of recently slaughtered cattle, defatted, were ground in a meat grinder until a homogeneous mass was obtained; to 1 kg. of homogenate was added 2 liters of the mixture of A, B, and C solution with vigorous stirrin To the mixture there was then added 1 g. of com- .pound No. 1 dissolved in 5.35 parts of propylenglycol;
the mixture was stirred at 28-37" C. for 3 hours, 13 liters of acetone were added and the mass was stirred at room temperature for an additional 1 hour. I
The acetone extract was separated by filtration, the ground adrenals were Washed with 6 liters of acetone, the extracts were combined and the solvent removed by distillation under reduced presure. Chromatography on alumina and crystallization of the 'solidfractions attracted-v 21-acetoxy-16a,17a-isopropylidenedioxy 2,19 cyclo-allopregnan-l1B-ol-3,20-dione (Cpd. No. 28). V
The Compounds Nos. 2 to 27, inclusive were treated according to the same procedure, thus affording respectively:
Cpd.
(29) 21-acetoxy-2,19-cyclo-allopregnane-l 15,17u-dil- 3,20-dione,
(30) 21-acetoxy-61a-methyl-2,l9-cyclo-allopregnane- 1 1fl,17a-diol-3,20-dione,
(31) 21-acetoxy-16a,17a-isopropylidenedioxy-Z,19-
cyclo-M-pregnen-l 1 ,8-ol-3,20-dione,
(3 2) 21-acetoxy-2,19-cyclo-A -pregnene-1 15,17a-di0l- 3 ,20-dione,
(3 3 21-acetoxy-16u-methyl-2,19-cyc1o-A -pregnene- 1 1;8,17m-dio1-3 ,20-dione,
(34) 21-acetoxy-6 3-chloro-16oz,17a-isopropylidenedioxy-Z,19-cyclo-A -pregnen-1 1 ,8-ol-3,20-dione,
(35) 21-acetoxy-6B-chloro-2,19-cyclo-A -pregnene- 115,17a-di0l-3 ,20-di0ne,
(3 6) 2 1-actoxy-6B-chloro-1 6u-methyl-2, 19-cyclo-A pregnene-1-1B,17a-diol-3 ,20-dione,
(37) 21-acetoxy-6/3-fluoro-16a,17a-isopropylidenedioxy-Z,19-cyclo-A -pregnen-1 1B-ol-3 ,20-dione,
(39) 21-acetoxy-6/3-fluoro-16a-rnethyl-2,19-cyclo-A pregnene-l 15,17a-di01-3 ,20-dione,
(40) 2l-acetoxy-6a-chloro-16a,17u-isopropylidenedioxy-Z,19-cyclo-A -pregnen-1 1p1-ol-3,20-dione,
(41 21-acetoxy-6a-chloro-2,19-cyclo-A -pregnene- 1 1B,17u-diol-3,20-dione.
(42) 21-acetoxy-6a-chloro-16a-methy1-2,19-cyclo-A pregnene-1 15,17a-di0l-3 ,ZO-dione.
(43 21-acetoxy-6u-fluoro-16a,17aisopropylidened-ioxy- 2,19-cyclo-A -pregnen-11fl-ol-3,20-dione.
(44) 21-acet0xy-6a-fluoro-2,19-cyclo-A -pregnene- 11B, l7a-di01-3 ,20-dione.
(46) 21-acetoxy-6-ch1oro-16a,17a-is0propylidenedioxy- 2,19-cyclo-A -pregnadien-1 15-01-3 ,20-dione.
(47) 21-acetoxy-6-ch1oro-2,19-cyc1o-A -pregnadiene- 11B,17a-dio1-3,20-dione.
(48) 21-acetoxy-6-chloro-1 6ot-methyl-2,19-cyclo-A pregnadiene-l1B,17a-dio1-3,20-dione.
(49) 21-acetoxy-6-fluoro-16a,17u-isopropylidenedioxy- 2,19-cyclo-A -pregnadien-1 15-ol-3,20-dione.
(50) 21-acetoxy-6-fluoro-2,19-cyclo-A -pregnadiene- 1 1,8,17a-diol-3 ,20-dione.
(51) 21-acetoxy-6-fluoro-16a-methyl-2,19-cyclo-A pregnadiene-l 113,17oc-di0l-3 ,20-dione.
( 52) 21-acet0xy-16u,17a-isopropylidenedioxy-2,19-
cyclo-A -pregnadien-1 1 ,B-ol-3,20-dione.
( 3 21-acetoxy-2,19-cyclo-A -pregnadiene-1 1,8,17a-
diol-3,20-dione.
(5 4) 21-acetoxy-16u-methyl-2,19-cyc1o-A -pregnadiene-l 16,17oc-di0l-3 ,20-dione.
Example III g. of 21-acetoxy-16a,17a-isopropylidenedioxy-2,19- cyclo-allopregnan-11,B-0l-3,20-dioue (Cpd. No. 28) was dissolved with slow heating in 125 cc. of dimethyl-formamide, the mixture was cooled, 4.2 g. of mesyl chloride and 5 cc. of pyridine were added and the solution was kept at 80 C. for half an hour. The reaction mixture was cooled, water was added and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from acetone-hexane furnished 21-acetoxy-16u,1 7a-isopropylidenedioxy 2,19 cyclo-A -allopregnene-3,20- dione (Cpd. No. 55).
2.8 g. of N-bromoaceta1nide were added to a mixture of 5 g. of the latter compound 50 cc. of pure dioxane and 0.8 cc. of 0.4 N perchloric acid While stirring in the dark at room temperature during 1 hour. The reaction mixture was stirred for 1 hour further, a solution of 10% sodium sulfite was then added until the potassium-starch indicator paper no longer turned blue, ice was added, the mixture was extracted with chloroform and the extract was washed consecutively with water, 5% aqueous sodium bicarbonate solution and water, and the solvent was removed by distillation under vacuo. By trituration of the residue with acetone there was obtained the corresponding 9a-bromo-1l/i-hydroxyallopregnane derivative.
A mixture of 4.5 g. of anhydrous potassium acetate and 45 cc. of acetone was heated almost to boiling and then a solution of 4.2 g. of the above bromohydrin in 45 cc. of acetone was added slowly while stirring; the mixture was then refluxed for 10 hours, cooled and almost all of the acetone was distilled off; iced-water was then added, the precipitate was filtered, washed with water and dried. Upon recrystallization from methylene chloride-benzene there was obtained 21-acetoxy-9;8,11B-oxido-16u,17u-isopropylidenedioxy 2,19 cyclo allopregnane-3,20-dione (Cpd. No. 56).
To a solution of 4 g. of the latter compound in 40 cc. of anhydrous chloroform, was added, over a period of 35 minutes, 30 cc. of a 0.45 N solution of dry hydrogen chloride in chloroform, under continuous stirring and maintaining the temperature around 0 C.: The mixture was then stirred at 0 C. for 1 hour further, diluted with water and the chloroform layer was separated, washed with aqueous sodium bicarbonate solution and then with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from acetone-hexane gave 21-acetoxy-9a-ch1oro-16u, 17oz isopropylidenedioxy 2,19 cyclo-allopregnan-llfiol-3,20-dione (Cpd. No. 57).
The Compounds Nos. 29 to 54, inclusive, were treated in accordance with the procedures described in Example 111 thus afi'ording firstly the corresponding M -derivatives, secondly the corresponding 9u-bromo-11B-hydroxy compounds, thirdly the corresponding 95,11p-oxido derivatives and then respectively the following compounds:
Cpd. No.:
(5 8) 21-acetoxy-9a-chloro-2, 19-cyclo-allopregnane-1 113,
17a-diol-3,20-dione,
(5 9) 21-acetoxy-9a-chloro-16a-methyl-2,19-cyclo-allopregnane-l 1,8,17u-di0l-3 ,ZO-dione,
( 60) 21-acetoxy-9a-chloro-16a,17u-isopropylidenedioxy- 2,19-cyclo-A -pregnen-1 1 B-ol-3,20-dione,
(61 21-acetoxy-9a-ch1oro-2,19 cyclo-A -pregnene-1 1 {3,
17a-dlOl-3,20-dl011 6,
(62) 21-acetoxy-9a-chloro-16a-methyl-2,19-cyclo-A pregnene-l 1,6,17u-diol-3 ,20-dione,
(63) 21-acetoxy-6/3,9a-dichloro-16a,17u-isopropylidenedioxy-Z,19-cyclo-A -pregnen-1 1,B-ol-3,20-dione,
( 64) 21-acetoxy-6fi,9a-dichloro-2,19-cyclo-A -pregnenel 1B,17a-diol-3,20-dione,
( 65) 21-acetoXy-6,8,9ot-dichloro-16a-methyl-2,19-cycle- A -pregnene-1 16', 1 7oc-diOl-3,20-di0l16,
(66) 21-acetoxy-6B-fiuoro-9a-chloro-1 6u,17u-isopropy1idenedioxy-Z,19-cyclo-A -pregnen-1 1 8-ol-3,20-dione,
(68) 21-acetoxy-6fl-fluoro-9ot-chloro-16ot-methyl-2, 19-
cyclo-M-pregnene-l1fi,17ot-diol-3,20-dione,
(69) 21-acetoxy-6a,9oc-dichloro-16a,17a-isopropylidenedioxy-2,19-cyclo-A -pregnen-1 1;8-01-3,20-dione,
(70) 21-acetoxy-6ot,9a-dichloro-2,19-cyclo-A -pregnene- 1 1B, l7a-diol-3,20-dione,'
(71 21-acetoxy-6a,9ot-dichloro-16ot-methyl-2,l9 cyclo M-pregnene-l 1}8,1706-dlO1-3,20-di0116,
(72) 21-acetoxy-6a-fluoro-9a-ch1oro-16u,17x-isopropylidenedioxy-Z,19-cyclo-A -pregnen-1 1 ,8-ol-3,20-dion'e,
(7 3 21-acetoxy-6ct-fluoro-9a-chloro-2,19-cycl0-A -preg-, nene-1 1,8, 1 7o-dio1-3,20-di0ne, V
(74) 21-acetoxy-601-fluoro 901-chloro-1601-methyl-2,19-
cyclo-A -pregnene-1 118,1701-dio1-3,20-dione,
(75 21-acetoxy-6,901-dichlor0-1601,1701-isopropylidenedioXy-2,19-cyclo-A -pregnadien-1 113-ol-3,20-dione, (76) 21-acetoXy-6,901-dichlor0-2,19-cyclo-A -pregnadiene-1113,1701-diol-3 ,2--dione,
( 77) 21-acetoXy-6,901-dich1oro-1601-methy1-2,19-cyclo- A -pregnadiene1 113, 1 701-diol-3,20-dione,
(78) 21-acetoxy-6rfluoro-9o1-chloro-1601,1701-isopropy1idenedioxy-Z,19-cyclo-A -pregnadien-1 1 13-ol-3,20-dione,
(79) 21-acetoxy-6-fiuoro-901-chloro-2,19-cyclo-A -pregnadiene-l 1 8,1701-diol-3,20-dione,
(80) 21-acetoxy-6-fluoro-901-ehloro-1601-rnethyl-2,19-cyclo-A -pregnadiene-l118,1701-diol-3,2O-dione,
(8 1 21-acetoxy-901-chloro-16 01,1 701-isopropylidenedioxy- 2,19-cyclo-A -pregnadien-1 15-01-3 ,20-dione,
(82) 21-acetoXy-9'u-chloro-2,19-cyclo-A -pregnadien- 1 113, 1701-dio1-3,20-dione,
(83 21-acet0Xy-901-chloro-1601-methyl-2,19-cyclo-A pregnadien-l 118,17a-diol-3,20-dione.
Example IV In a polyethylene flask, adapted with magnetic stirrer, there was dissolved 1.8 g. of 21-acetoxy-913,1113-oxido- 1601,1701 isopropylidenedioxy 2,19 cyclo allopregnane-3,20-di0ne (Cpd. No. 56), in 30 cc. of methylene chloride, the solution was cooled to 0 C. and a solution of 2.11 g. of anhydrous hydrogen fluoride in 3.7 cc. of tetrahydrofurane cooled in a Dry-Ice acetone bath (70 C.) was added over a period of 20 minutes with constant stirring. The mixture was stirred at a temperature lower than C. for 6 additional hours, then 'neutralized by cautiouslyadding a 5% aqueous sodium bicarbonate solution and transferred to a separatory funnel. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated until formation of an abundant precipitate. The mixture was cooled, the precipitate filtered and redissolved in hot ethyl acetate, the insoluble material was filtered off and the filtrate cooled whereby the recrystallized 21-acetoxy-901-fluoro- 1601,1701 isopropylidenedioxy 2,19 cyclo allopregnane-1113-ol-3,20-dione (Cpd. No. 84).
The Compounds Nos. 29 to 54, inclusive, were converted into the corresponding 9 3,1113-oXido compounds, in accordance with Example 111, which, in turn, were treated by the above described procedure, thus affording respectively Cpd. No.:
(85) 21 acetoxy 901 fluoro 2,19 cyclo allopregname-1113, 17 01-diol-3 ,ZO-dione,
(86) 21 acetoxy 901 fluoro 1601 methyl 2,19-
cyclo-allopregnane-l113,1701-diol-3,20-dione,
(87) 21 acetoxy 901 fluoro 1611,1701 isopropylidenedioxy-2,19-cyclo-A -pregnene-1 113-01-3 ,20-dione,
(88) 21 acetoxy 901 fluoro 2,19 cyclo A pregnene-l15,1701.-di0l-3,20-di0ne,
(89) 21 acetoxy 901 fluoro 16a methyl 2,19-
cyclo-M-pregnene-l 113,17 01-di0l-3 ,20-dione,
(90) 21 acetoxy 6 3 chloro 901 fluoro 16,1701- isopropylidenedioxy 2,19 cyclo A pregnen 11 3- ol-3,20-dione, v e
(91) 21 acetoxy 613 chloro- 901 iuoro 2,19 cyclo- -pregnene-11 6,1701-diol-3 ,20-dione.
(92) 21 acetoxy 613 chloro 901 fluoro 1611 methyl- 2,19 cyclo A pregnene 11,6,1701 diol 3,20- dione,
(93) 21 acetoxy 613,901 difiuoro 1601,1701 isopropylidenedioxy 2,19 cyclo A pregnen 1113 ol- 3,20-dione,
(94) 21 acetoxy 613,901 difluoro 1 2,19 cyclo A pregnene-l 113,1701-diol-3,20-dione,
(95) 21 acetoxy 613,901 difluoro 1601 methyl 2,19-
cyclo-M-pregnene-l 113,1701-diol-3 ,20-dione,
(96) 21 aceto-xy 601 chloro 901 fluoro 1601,1701 isopropylidenedioxy 2,19 cyclo A pregnen 1113-1 ol-3,20-dione,
(97) 21 acetoxy 601 chloro 901 fluoro 2,19 cyclo- -pregnene-1 13,171z-di0l-3 ,ZO-dione,
(98) 21 acetoxy 601 chloro 901 fluoro 1601 methyl- 2,19 cyclo A pregnene 1113,17 01. diol 3,20 dione.
(99) 21 acetoxy 601,901 difluoro 1601,1701 isopropylidenedioxy-Z,19-cyclo-A -pregnen-1 1B-ol-3,20-di0ne,
(100) 21 acetoxy 601,901 difluoro 2,19 cyclo A pregnene-l11i,1701-diol-3,20-dione,
(101) 21 acetoxy 601,900 difluoro 1601 methyl 2,19-
cyclo-M-pregnene-l113,1701-diol-3,20-dione,
(102) 21 acetoxy 6 chloro 901 fluoro 1601,1701- isopropylidenedioxy 2,19 cyclo A pregnadien- 1113-ol-3,20-dione,
(103) 21 acetoxy 6 chloro 901 fluoro 2,19 cyclo- A -pregnadiene-l1,3,1701-di0l-3 ,20-di0ne,
(104) 21 acetoxy 6 chloro 901 fluoro 1601 methyl- 2,19 cyclo A pregnadiene 116,1701 diol 3,20 dione,
(105) 21 acetoxy 6,901 difluoro 1601,1701 isopropylidenedioxy 2,19 cyclo A pregnadien 1113- ol-3,20-dione,
(106) 21 acetoxy 6,901 difluoro 2,19 cyclo A pregnadiene-l113,1701-diol-3,20-dione,
(107) 21 acetoxy 6,901 difluoro 1601. methyl 2,19-
cyclo-A -pregnadiene-1 113, 17a-diol-3,20-dione,
(108) 21 acetoxy 901 fluoro 1601,1701 isopropylidenedioxy 2,19 cyclo A pregnadien 1113 ol- 3,20-dione,
(109) 21 acetoxy 901 fluoro 2,19 cyclo A pregnadiene-l 1 3-1701-diol-3,20-dione,
(110) 21 acetoxy 901 fluoro 1601 methyl 2,19-
cyclo-A -pregnadiene-1 1 8,1701-diol-3,20-dione,
Example V A solution of 1 g. of 21-acetoxy-16a,-1701-isopropylidenedioxy-Z,19-cyclo-allopregnan-1113-ol-3,20-di0ne (Cpd. No. 28) in 10 cc. of acetone was cooledto 0 C. and treated under an atmosphere of nitrogen and with stirring, with a solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture. It was stirred for 5 minutes further at 0-5" C. and diluted with water. The precipitate was collected, washed with water and dried under vacuum, thus affording a crude product which upon recrystallization from acetone-hexane gave 21 acetoxy 1601,1701-isopropylidenedioXy-2,19-cycloallopregnane-3,11,20-trione (Cpd. No. 111).
The Compounds Nos. 29 to 54, inclusive, were treated in accordance with the above procedure, thus yielding respectively:
Cpd. No.:
(118) 21-acetoxy-613-chloro-2,19-cyclo-A -pregnen-1701- 01-3, 1 1,20-trione, 1 19) 21-acct0xy- 613-cl1loro-1-601-methyl-2,19-cyclo-A pregnen-1701-ol-3,1 1,20-trione,
Example XI 1 g. of 160:,170: isopropylidenedioxy 2,19 cyclo allopregnane-l1 3,21-diol-3,20-dione (Cpd. No. 192) was heated on the steam bath with 100 cc. of 80% acetic acid under nitrogen for 7 hours, it was then concentrated under vacuum to a small volume and poured into water. The precipitate was collected, washed well with water, dried and recrystallized from acetone-hexane, thus furnishing 2,19 cyclo allopregnane 11/3,l6oc,17oz,21 tetrol-3,20-dione (Cpd. No.- 247).
Following the same procedure there were treated the Compounds Nos. 195, 204, 207, 210, 213, 216, 219, 222, 231, 237, and 243, thus producing respectively:
Cpd. No.:
The Compounds Nos. 57, 60, 84, and 105 were treated according to the procedure described in Example XI, thus affording the corresponding free 16a,17a-diols.
Example XIII The Compounds Nos. 247, 248 and 249 were treated in accordance with Example X, thus giving respectively:
Cpd. No.:
(259) 2,19 cyclo allopregnane 1l,l3,l6u,17a,21 tetrol- 3,20-dione 16,21-dicaproate,
(260) 2,19 cyclo A pregnene l1,B,16oc,l7ot,21 tetrol-3,20-dione, 16,21-dicaproate,
(261) 6a chloro 2,19 cyclo A pregnene 11,19,161,
17u,21-tetrol-3,20-dione 16,2l-dicaproate.
Example XIV A mixture of 1 g. of Compound No. 247, 50 cc. of freshly distilled acetophenone and 0.5 cc. of 72% perchloric acid was stirred at room temperature for 1 hour. The resulting mixture was washed with sodium bicarbonate solution and with water to neutrality, then it wassteam distilled and the product extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane yielded the 16,17-acetophenonide of 2,19- cyclo allopregnane 11,8,16oc,l7oc,21 tetrol 3,20 dione (Cpd. No. 262).
By the same procedure, there were obtained the 16.17- acetophenonides of Compounds Nos. 248 to 258, inclusive.
I claim:
1. A compound of the following formula:
wherein Y is selected from the group consisting of hydrogen, fiuorine and chlorine; W is selected from the group consisting of a B-hydroxyl group and a keto group; X is a member of the group consisting of hydrogen, (X-fluO- rine, fl-fluorine, a-chlorine and fl-chlorine; Z is selected from the group consisting of a double bond and a saturated linkage between C-4 and C-5; Z is selected from the group consisting of a double bond and a saturated linkage between C-6 and C-7, and when Z is a saturated linkage, Z is a saturated linkage; R is a hydroxyl group; T is selected from the group consisting of hydrogen, t-hydroxyl, tat-hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms, u-methyl and B-methyl; T and R together form the group in the 16a,17a-positions wherein R and R are selected from the group consisting of hydrogen and a hydrocarbon residue of up to 8 carbon atoms; and R is selected from the group consisting of hydrogen and hydrocarbon carboxylic acyl group of less than 12 carbon atoms.
2. 21 acetoxy 16a,17a isopropylidenedioxy 2,19- cyclo-allopregnan-l 1B-ol-3,20-dione.
3. 21 acetoxy 2,19 cyclo allopregnane 113,170:- dio1-3,20-dione.
4. 2-1 acetoxy 16a methyl 2,19 cyclo allopregnane-l 1;3,17a-diol-3,20-dione.
5. 21 acetoxy 160:,1711 isopropylidenedioxy 2,19- cyclo-A pregnen-l 1;3-ol-3,20-dione.
6. 21'- acetoxy 2,19 cyclo A pregnene 115,170:- diol-3,20-dione.
7. 21 acetoxy 16a methyl 2,19 cyclo A pregnene-11/3,17a-diol-3,20-dione.
8. 21 acetoxy 160L,17oc isopropylidenedioxy 2,19 cyclo-allopregnane-3,11,20-trione.
9. 21 acetoxy 16oz methyl 2,19 cyclo-allopregnan- 10. 21 acetoxy 2,19 cyclo allopregnan 17a ol- 3,11,20-trione.
11. 21 acetoxy 2,19 cyclo A pregnen 17cc ol- 3,11,20-tri0ne.
12. 2-1 acetoxy 160a methyl 2, 19 cyclo A preg- I16l1-17oz-Ol-3,l1,20-t1i0n6.
13. 21 acetoxy 160:,l7a isopropylidenedioxy 2,19- cyclo-A -pregnene-3,1-1,20-trione.
14. 21- acetoxy 6a,9a dichloro l6oc,17oc isopropylidenedioxy-2;19-cyclo-A -pregnen-1 1,8-ol-3,20-dione.
15. 21 acetoxy 6a fiuoro c chloro 16u,17a-

Claims (1)

1. A COMPOUND OF THE FOLLOWING FORMULA:
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